DESCRIPTION: (Applicant's Abstract) High-dose chemotherapy with autologous hematopoietic progenitor cell support is effective treatment for selected patients with high-risk breast cancer. Major limitations of this therapeutic strategy include 1) potential breast cancer cell contamination of the autologous hematopoietic cell grafts; 2) myelosuppression induced morbidity and mortality; and 3) incomplete eradication of breast cancer in the majority of patients with stage IV disease. The applicant's initial grant began to address these limitations by conducting clinical studies evaluating the purification of hematopoietic progenitor cells. This renewal application will continue on that path by pursuing several different strategies. Aim 1 will continue to focus on the development and clinical evaluation of optimal methods for removing breast cancer cells from the autografts. Aim 2 is directed at improving the ability to detect breast cancer cells in the autografts, particularly those with clonogenic potential, and assess their impact on post transplant relapse of disease. Aim 3 will evaluate the ex vivo expansion of hematopoietic cells as a breast cancer purging strategy and as a method to reduce the period of high-dose therapy-induced myelosuppression in the allogeneic transplant setting. Aim 4 is directed toward developing a clinically relevant mouse assay to potentially predict the performance of manipulated hematopoietic progenitors in the applicant's patients. The data generated by the preclinical investigations and the proposed clinical studies will enable her to devise the more efficacious strategies for treating women with poor prognosis breast cancer. The innovative aspects of this application include the use of ex-vivo expansion as a purging strategy to eradicate breast cancer from autografts and the use of expanded allogeneic cord blood support for patients who are not good candidates for autologous transplants. Neither strategy has been employed previously, and both have the potential to substantially improve the clinical outcome of patients with breast cancer. The applicant's group has a proven track-record of transitional research productivity in the area of hematopoietic cell supported therapy of breast cancer patients, and will very likely be able to answer the questions proposed in this renewal application.